Abstract LB302: Radiotherapy exposure and baseline gut microbiota predict clinical outcomes of fruquintinib plus sintilimab in microsatellite-stable metastatic colorectal cancer
Authors: Min Jin, Mingxia Cheng, Shengli Yang, Lei Zhao, Dandan Yu, Zhenyu Lin, Pindong Li, Jing Wang, Jun Xue, Hong Ma, Jianli Hu, Tao Zhang, Hongli Liu
Journal: Cancer Research (2023)

Abstract Background: Clinical trials demonstrated that immune checkpoint inhibitors (ICIs) combined with antiangiogenic drugs had achieved promising outcomes in the third-line and further treatment in metastatic colorectal cancer (mCRC) patients (pts) with microsatellite-stable (MSS) or proficient mismatch repair. Radiotherapy (RT) may enhance the anti-tumor effect of immunotherapy. However, the outcomes of RT on pts receiving targeted therapy plus ICIs remains unclear. Therefore, this study was aimed to investigate the association between RT exposure and clinical responses to fruquintinib plus sintilimab (F&amp;S) in previously treated MSS-CRC and explore predictive biomarkers. Methods: This prospective observational cohort study assessed treatment outcomes of F&amp;S as the third- or further-line therapy for advanced CRC pts at Wuhan Union Hospital from Mar 2021 to Jun 2022 (NCT05635149). The pts were divided into two cohorts according to their RT history. The objective response rate (ORR) was set as the primary endpoint. We collected pre-treatment stool samples from pts for microbiota sequencing. Results: A total of 55 pts were enrolled, of whom 25 pts received prior RT (RT cohort, RTC) and the other 30 pts had no exposure to RT (non-RT cohort, NRTC). Globally, the objective response rate (ORR) was 18.0%, the DCR was 56.3%, and the median PFS (mPFS) was 3.6 mo. When compared between the two cohorts, the ORR was 28.0% vs. 6.7% (OR=7.344, P=0.039, RTC vs. NRTC, the same hereinafter), the DCR was 80.0% vs. 36.7% (OR=7.991, P=0.010), and the mPFS was 6.1 mo vs. 2.6 mo (HR=0.286, P&amp;lt;0.001). Multivariate COX regression showed that RT was an independent factor on the PFS. Overall, 27 (49.1%) pts experienced grade 1 or 2 adverse events (AEs), and grade 3 AEs were observed in 7 (12.7%) pts. The most common AEs included hepatotoxicity, hypertension and hand-foot syndrome. Moreover, analysis of gut microbiome (n=20) showed there was also significant difference in mPFS of pts in RTC (n=8) versus NRTC (n=12) (6.1 mo vs. 3.1 mo, P=0.002). Bifidobacterium and lactobacillus enriched significantly in RTC at the genus level, and further ROC curve identified the coexistence of bifidobacteria and lactobacillus enrichment predicted greater DCR (AUC=0.909), enhancing their potential as biomarkers for response. Furthermore, we found that high abundance of lactobacillus was also strongly associated with prolonged PFS (P=0.043). Conclusion: In this study, we found that pts with RT exposure could benefit more from F&amp;S as the third- or further-line therapy in MSS colorectal cancer. Furthermore, bifidobacteria and lactobacillus enriched in baseline stool samples from pts in RTC, which may be potential biomarkers for outcomes. Further studies with larger scale sample size are warranted to validate our findings. Citation Format: Min Jin, Mingxia Cheng, Shengli Yang, Lei Zhao, Dandan Yu, Zhenyu Lin, Pindong Li, Jing Wang, Jun Xue, Hong Ma, Jianli Hu, Tao Zhang, Hongli Liu. Radiotherapy exposure and baseline gut microbiota predict clinical outcomes of fruquintinib plus sintilimab in microsatellite-stable metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB302.